Potent
Next-generation Experimental Integrase Inhibitor S/GSK1349572 Debuts
at IAS 2009
 | S/GSK1349572
is a novel new integrase inhibitor (INI) that has demonstrated potent antiviral
activity in laboratory studies, human pharmacokinetics (PK) that support once
daily dosing, and a favorable safety profile. Results of 5 studies of the drug
were presented at IAS 2009 conference in Cape Town. This review summarizes the
outcomes of the one clinical study presented, a short monotherapy study in HIV
patients that demonstrates the "unprecedented antiviral activity" of the drug
and its "superior resistance profile," according to the study authors. |
By
Ronald Baker, PhD Shionogi
of Japan and GlaxoSmithKline have partnered in a joint venture to develop next-generation
integrase inhibitors, which led to their selection of S/GSK1349572 as their lead
candidate for development. The drug is the only once daily, unboosted integrase
inhibitor currently in development. Study
Methods  | This
was a Phase 2 dose ranging, placebo-controlled study of S/GSK1349572 in 35 INI-naïve
HIV-1 infected adults who were not currently receiving antiretroviral therapy.
| | Participants
had HIV RNA of greater than or equal to 5000 copies/ml and CD4 greater than or
equal to 100 cells/mm3. | | They
were randomized to doses of 2mg, 10mg, 50mg or placebo once daily. | | HIV-1
RNA, genotypes/phenotypes, safety labs, vital signs, ECGs and PK sampling were
performed. |
Results | Thirty-five
people completed all study visits. | | Demographics
were similar across treatment groups. | | There
were no deaths or severe adverse events (SAEs). | | No
patients withdrew from the study due to an adverse event (AE). | | Diarrhea,
fatigue and headache were the most commonly reported AEs (except for headache,
which was more common in the placebo group). | | Similar
AE rates were observed in S/GSK1349572 and placebo groups | | Most
AEs were mild to moderate. | | No
clinically significant trends were noted in laboratory abnormalities, vital signs
or ECG values. | | A
mean decrease from baseline on Day 11 in plasma HIV-1 RNA of 1.51 to 2.46 log10
copies/mL was observed across the S/GSK1349572 doses tested (2mg - 50mg) compared
with placebo. | | At
the 50mg dose, 70% of participants achieved undetectable plasma HIV-1 RNA levels
(< 50 copies/mL). | | No
S/GSK1349572 phenotypic resistance was noted. | | No
signature substitutions associated with in vivo raltegravir or elvitegravir
clinical resistance or with S/GSK1349572 in vitro passage were detected. |
Authors'
Conclusions | S/GSK1349572
is a potent inhibitor of HIV integrase. | | S/GSK1349572
had limited cross-resistance to raltegravir and elvitegravir resistant virus. | | S/GSK1349572
was generally well-tolerated and demonstrated unprecedented anti-HIV activity
following short-term, once-daily, unboosted dosing in INI-naïve patients.
| | These
data support progression into phase 2b clinical trials. |
ING111521
Investigators, Research Triangle Park, United States, GlaxoSmithKline, Research
Triangle Park, United States, Shionogi & Co., Ltd., Osaka, Japan, GlaxoSmithKline,
Infectious Diseases Medicine Development Center, Research Triangle Park, United
States. To
view posters and or slides from the five studies on S/GSK1349572 presented at
IAS 2009, visit the IAS
2009 Library of Slides and Posters on the IAS 2009 Conference Main Page on
HIV and Hepatitis.com Editor's
Note: In a teleconference following the study presentation, GSK said
that two phase 2b studies of S/GSK1349572 will start in late July 2009, one in
treatment-naïve patients and the other in treatment-experienced patients.
Further, the company expects phase 3 studies to start by the end of 2009. 7/24/09 Reference
J Lalezari, L Sloan, E Dejesus, and others . Potent antiviral activity
of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naïve
HIV-1-infected patients. 5th International AIDS Society Conference on HIV Pathogenesis,
Treatment and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa.
Abstract TUAB105.
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